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    Summary
    EudraCT Number:2019-000944-82
    Sponsor's Protocol Code Number:MK-3475-966
    National Competent Authority:Spain - AEMPS
    Clinical Trial Type:EEA CTA
    Trial Status:Ongoing
    Date on which this record was first entered in the EudraCT database:2019-07-26
    Trial results
    Index
    A. PROTOCOL INFORMATION
    B. SPONSOR INFORMATION
    C. APPLICANT IDENTIFICATION
    D. IMP IDENTIFICATION
    D.8 INFORMATION ON PLACEBO
    E. GENERAL INFORMATION ON THE TRIAL
    F. POPULATION OF TRIAL SUBJECTS
    G. INVESTIGATOR NETWORKS TO BE INVOLVED IN THE TRIAL
    N. REVIEW BY THE COMPETENT AUTHORITY OR ETHICS COMMITTEE IN THE COUNTRY CONCERNED
    P. END OF TRIAL
    Expand All   Collapse All
    A. Protocol Information
    A.1Member State ConcernedSpain - AEMPS
    A.2EudraCT number2019-000944-82
    A.3Full title of the trial
    A Phase 3 Randomized, Double Blind Study of Pembrolizumab Plus Gemcitabine/Cisplatin versus Placebo Plus Gemcitabine/Cisplatin as First-Line Therapy in Participants with Advanced and/or Unresectable Biliary Tract Carcinoma
    Estudio de fase 3, aleatorizado y doble ciego de pembrolizumab más gemcitabina/cisplatino en comparación con placebo más gemcitabina/cisplatino como tratamiento de primera línea en participantes con carcinoma de vías biliares avanzado o irresecable
    A.3.1Title of the trial for lay people, in easily understood, i.e. non-technical, language
    Pembrolizumab or Placebo Plus Gemcitabine/Cisplatin for First-Line Advanced and/or Unresectable BTC
    Pembrolizumab o placebo más gemcitabina/cisplatino en el tratamiento de primera línea del CVB avanzado o irresecable.
    A.4.1Sponsor's protocol code numberMK-3475-966
    A.5.4Other Identifiers
    Name:INDNumber:123482
    A.7Trial is part of a Paediatric Investigation Plan No
    A.8EMA Decision number of Paediatric Investigation Plan
    B. Sponsor Information
    B.Sponsor: 1
    B.1.1Name of SponsorMerck Sharp & Dohme Corp., a subsidiary of Merck & Co., Inc.
    B.1.3.4CountryUnited States
    B.3.1 and B.3.2Status of the sponsorCommercial
    B.4 Source(s) of Monetary or Material Support for the clinical trial:
    B.4.1Name of organisation providing supportMerck Sharp & Dohme Corp., a subsidiary of Merck & Co., Inc.
    B.4.2CountryUnited States
    B.5 Contact point designated by the sponsor for further information on the trial
    B.5.1Name of organisationMerck Sharp & Dohme de España SA
    B.5.2Functional name of contact pointInvestigación Clínica
    B.5.3 Address:
    B.5.3.1Street AddressCalle Josefa Valcárcel nº 38
    B.5.3.2Town/ cityMadrid
    B.5.3.3Post code28027
    B.5.3.4CountrySpain
    B.5.4Telephone number+3491 321 06 00
    B.5.5Fax number+3491 321 05 90
    B.5.6E-mailensayos_clinicos@merck.com
    D. IMP Identification
    D.IMP: 1
    D.1.2 and D.1.3IMP RoleTest
    D.2 Status of the IMP to be used in the clinical trial
    D.2.1IMP to be used in the trial has a marketing authorisation No
    D.2.5The IMP has been designated in this indication as an orphan drug in the Community No
    D.2.5.1Orphan drug designation number
    D.3 Description of the IMP
    D.3.1Product namepembrolizumab
    D.3.2Product code MK-3475
    D.3.4Pharmaceutical form Solution for infusion
    D.3.4.1Specific paediatric formulation No
    D.3.7Routes of administration for this IMPIntravenous use
    D.3.8 to D.3.10 IMP Identification Details (Active Substances)
    D.3.8INN - Proposed INNPEMBROLIZUMAB
    D.3.9.1CAS number 1374853-91-4
    D.3.9.2Current sponsor codeMK-3475
    D.3.9.4EV Substance CodeSUB167136
    D.3.10 Strength
    D.3.10.1Concentration unit mg/ml milligram(s)/millilitre
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number25
    D.3.11 The IMP contains an:
    D.3.11.1Active substance of chemical origin No
    D.3.11.2Active substance of biological/ biotechnological origin (other than Advanced Therapy IMP (ATIMP) Yes
    The IMP is a:
    D.3.11.3Advanced Therapy IMP (ATIMP) No
    D.3.11.3.1Somatic cell therapy medicinal product No
    D.3.11.3.2Gene therapy medical product No
    D.3.11.3.3Tissue Engineered Product No
    D.3.11.3.4Combination ATIMP (i.e. one involving a medical device) No
    D.3.11.3.5Committee on Advanced therapies (CAT) has issued a classification for this product No
    D.3.11.4Combination product that includes a device, but does not involve an Advanced Therapy No
    D.3.11.5Radiopharmaceutical medicinal product No
    D.3.11.6Immunological medicinal product (such as vaccine, allergen, immune serum) Yes
    D.3.11.7Plasma derived medicinal product No
    D.3.11.8Extractive medicinal product No
    D.3.11.9Recombinant medicinal product Yes
    D.3.11.10Medicinal product containing genetically modified organisms No
    D.3.11.11Herbal medicinal product No
    D.3.11.12Homeopathic medicinal product No
    D.3.11.13Another type of medicinal product No
    D.IMP: 2
    D.1.2 and D.1.3IMP RoleTest
    D.2 Status of the IMP to be used in the clinical trial
    D.2.1IMP to be used in the trial has a marketing authorisation Yes
    D.2.1.1.1Trade name Keytruda (pembrolizumab, MK-3475)
    D.2.1.1.2Name of the Marketing Authorisation holderMerck Sharp & Dohme B.V.
    D.2.1.2Country which granted the Marketing AuthorisationEuropean Union
    D.2.5The IMP has been designated in this indication as an orphan drug in the Community No
    D.2.5.1Orphan drug designation number
    D.3 Description of the IMP
    D.3.4Pharmaceutical form Solution for infusion
    D.3.4.1Specific paediatric formulation No
    D.3.7Routes of administration for this IMPIntravenous use
    D.3.8 to D.3.10 IMP Identification Details (Active Substances)
    D.3.8INN - Proposed INNPEMBROLIZUMAB
    D.3.9.1CAS number 1374853-91-4
    D.3.9.2Current sponsor codeMK-3475
    D.3.9.4EV Substance CodeSUB167136
    D.3.10 Strength
    D.3.10.1Concentration unit mg/ml milligram(s)/millilitre
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number25
    D.3.11 The IMP contains an:
    D.3.11.1Active substance of chemical origin No
    D.3.11.2Active substance of biological/ biotechnological origin (other than Advanced Therapy IMP (ATIMP) Yes
    The IMP is a:
    D.3.11.3Advanced Therapy IMP (ATIMP) No
    D.3.11.3.1Somatic cell therapy medicinal product No
    D.3.11.3.2Gene therapy medical product No
    D.3.11.3.3Tissue Engineered Product No
    D.3.11.3.4Combination ATIMP (i.e. one involving a medical device) No
    D.3.11.3.5Committee on Advanced therapies (CAT) has issued a classification for this product No
    D.3.11.4Combination product that includes a device, but does not involve an Advanced Therapy No
    D.3.11.5Radiopharmaceutical medicinal product No
    D.3.11.6Immunological medicinal product (such as vaccine, allergen, immune serum) Yes
    D.3.11.7Plasma derived medicinal product No
    D.3.11.8Extractive medicinal product No
    D.3.11.9Recombinant medicinal product Yes
    D.3.11.10Medicinal product containing genetically modified organisms No
    D.3.11.11Herbal medicinal product No
    D.3.11.12Homeopathic medicinal product No
    D.3.11.13Another type of medicinal product No
    D.8 Information on Placebo
    D.8 Placebo: 1
    D.8.1Is a Placebo used in this Trial?Yes
    D.8.3Pharmaceutical form of the placeboSolution for infusion
    D.8.4Route of administration of the placeboIntravenous use
    E. General Information on the Trial
    E.1 Medical condition or disease under investigation
    E.1.1Medical condition(s) being investigated
    Advanced and/or Unresectable Biliary Tract Carcinoma (Intrahepatic, Extrahepatic, or Gallbladder)
    Avanzado y/o irresecable carcinoma de vías biliares ((intrahepática, extrahepáticas, o de la vesícula biliar)
    E.1.1.1Medical condition in easily understood language
    Advanced (metastatic) and/or unresectable (locally advanced) biliary tract cancer (intra-or extrahepatic cholangiocarcinoma or gallbladder cancer).
    Avanzado (metastásico) o irresecable (localmente avanzado) cáncer del tracto biliar colangiocarcinoma intra- o extrahepático o cáncer de vesícula biliar).
    E.1.1.2Therapeutic area Diseases [C] - Cancer [C04]
    MedDRA Classification
    E.1.2 Medical condition or disease under investigation
    E.1.2Version 20.0
    E.1.2Level LLT
    E.1.2Classification code 10004655
    E.1.2Term Biliary carcinoma
    E.1.2System Organ Class 100000004864
    E.1.3Condition being studied is a rare disease No
    E.2 Objective of the trial
    E.2.1Main objective of the trial
    1. To compare progression-free survival (PFS) per Response Evaluation Criteria in Solid Tumors Version 1.1 (RECIST 1.1), as assessed by Blinded Independent Central Review (BICR), between pembrolizumab plus gemcitabine/cisplatin and placebo plus gemcitabine/cisplatin
    2. To compare overall survival (OS) between pembrolizumab plus gemcitabine/cisplatin and placebo plus gemcitabine/cisplatin
    1. Comparar la supervivencia sin progresión (SSP) conforme a los criterios RECIST 1.1, según una revisión centralizada independiente y enmascarada (RCIE), entre pembrolizumab más gemcitabina/cisplatino y placebo más gemcitabina/cisplatino
    2. Comparar la supervivencia global (SG) entre pembrolizumab más gemcitabina/cisplatino y placebo más gemcitabina/cisplatino
    E.2.2Secondary objectives of the trial
    1. To compare objective response rate (ORR) per Response Evaluation Criteria in Solid Tumors Version 1.1 (RECIST 1.1), as assessed by Blinded Independent Central Review (BICR), between pembrolizumab plus gemcitabine/cisplatin and placebo plus gemcitabine/cisplatin
    2. To evaluate duration of response (DOR) per Response Evaluation Criteria in Solid Tumors Version 1.1 (RECIST 1.1) as assessed by Blinded Independent Central Review (BICR)
    3. To evaluate the safety and tolerability profile of pembrolizumab plus gemcitabine/cisplatin
    1. Comparar la tasa de respuestas objetivas (TRO) conforme a los criterios RECIST 1.1, según una RCIE, entre pembrolizumab más gemcitabina/cisplatino y placebo más gemcitabina/cisplatino
    2. Evaluar la duración de la respuesta (DR) conforme a los criterios RECIST 1.1, según una RCIE.
    3. Evaluar el perfil de seguridad y tolerabilidad de pembrolizumab más gemcitabina/cisplatino
    E.2.3Trial contains a sub-study Yes
    E.2.3.1Full title, date and version of each sub-study and their related objectives
    Sponsor will conduct Future Biomedical Research on DNA (blood, tumor material) specimens collected during this clinical trial. Such research is for biomarker testing to address emergent questions not described elsewhere in the protocol (as part of the main trial) and will only be conducted on specimens from appropriately consented subjects. The objective of collecting specimens for Future Biomedical Research is to explore and identify biomarkers that inform the scientific understanding of diseases and/or their therapeutic treatments. The overarching goal is to use such information to develop safer, more effective drugs, and/or to ensure that subjects receive the correct dose of the correct drug at the correct time
    El Promotor llevará a cabo futuras investigaciones biomédicas sobre muestras de ADN (sangre, material tumoral) recogidas durante este ensayo clínico. Dicha investigación es para pruebas de biomarcadores para abordar preguntas emergentes no descritas en otra parte del protocolo (como parte del ensayo principal) y sólo se llevará a cabo en muestras de sujetos que hayan consentido debidamente. El objetivo de la recogida de muestras para las Futuras Investigaciones Biomédicas es explorar e identificar biomarcadores que informen la comprensión científica de las enfermedades y/o sus tratamientos terapéuticos. El objetivo general es utilizar dicha información para desarrollar medicamentos más seguros y/o más eficaces, y/o para asegurar que los sujetos reciban la dosis correcta del medicamento correcto en el momento correcto.
    E.3Principal inclusion criteria
    1. Has histologically confirmed diagnosis of advanced (metastatic) and/or unresectable (locally advanced) biliary tract cancer (intra-or extrahepatic cholangiocarcinoma or gallbladder cancer).
    2. Have measurable disease based on RECIST 1.1, as determined by the site investigator. Lesions situated in a previously treated area by either radiotherapy, photodynamic therapy, or arterial embolization are considered measurable if progression has been demonstrated in such lesions and they meet criteria for measurable disease.
    3. Participants with past or ongoing HCV infection are eligible for the study. Treated participants must have completed their treatment at least 1 month prior to starting study intervention. Untreated or incompletely treated HCV participants may initiate anti-viral therapy for HCV if liver function remains stable for at least 3 months on study intervention.
    4. Participants with controlled hepatitis B are eligible for the study , as long as they meet the following criteria:
    - Participants with chronic HBV infection, defined as HBsAg positive and/or detectable HBV DNA, must be given antiviral therapy for HBV for at least 4 weeks prior to the first dose of study intervention and HBV viral load must be less than 100 IU/mL prior to first dose of study treatment. Participants on active HBV therapy with viral loads under 100 IU/mL should stay on the same therapy throughout study intervention. Antiviral therapy after completion of study intervention should follow local guidelines.
    - Participants with clinically resolved HBV infection, defined as HBsAg negative and anti-HBc positive, and who have an undetectable HBV viral load at screening should be checked every 6 weeks for HBV viral load and treated for HBV if viral load is over 100 IU/mL. Antiviral therapy after completion of study intervention should follow local guidelines.
    5. Is male or female, from at least 18 years of age inclusive, at the time of signing the informed consent.
    6. Male participants are eligible to participate if they agree to the following during the intervention period and for at least and through 120 days after the last dose of chemotherapy:
    • Refrain from donating sperm, PLUS either:
    • Be abstinent from heterosexual intercourse as their preferred and usual lifestyle (abstinent on a long term and persistent basis) and agree to remain abstinent OR
    • Must agree to use contraception unless confirmed to be azoospermic.
    • Male participants must also agree to use a male condom when engaging in any activity that allows for passage of ejaculate to another person of any sex.
    7. A female participant is eligible to participate if she is not pregnant or breastfeeding, and at least one of the following conditions applies:
    - Is not a woman of childbearing potential (WOCBP) OR
    - Is a WOCBP and using a contraceptive method that is highly effective (with a failure rate of <1% per year), with low user dependency, or be abstinent from heterosexual intercourse as their preferred and usual lifestyle (abstinent on a long term and persistent basis), as described in the Protocol
    - A WOCBP must have a negative highly sensitive pregnancy test (urine or serum, as required by local regulations) within 24 hours before the first dose of study intervention.
    - If a urine test cannot be confirmed as negative (eg, an ambiguous result), a serum pregnancy test is required. In such cases, the participant must be excluded from participation if the serum pregnancy result is positive.
    8. The participant (or legally acceptable representative, if applicable) provides written informed consent for the study.
    9. Have a performance status of 0 or 1 on the ECOG Performance Scale within 3 days prior to the first dose of study intervention.
    10. Provide archival tumor tissue sample or newly obtained core or excisional biopsy of a tumor lesion not previously irradiated (ie, obtained for histological confirmation) for biomarker analysis. The tumor tissue must be received by the central vendor and be deemed adequate for biomarker analysis evaluation prior to participant randomization. Formalin fixed, paraffin-embedded (FFPE) tissue blocks are preferred to slides. Newly obtained biopsies are preferred to archived tissue.

    Read in the protocol
    1. Diagnóstico confirmado histológicamente de cáncer de vías biliares (colangiocarcinoma intra o extrahepático o cáncer de vesícula biliar) avanzado (metastásico) o irresecable (localmente avanzado)
    2. Enfermedad mensurable conforme a los criterios RECIST 1.1, según la evaluación del investigador del centro. Las lesiones ubicadas en una zona previamente irradiada por radioterapia, terapia fotodinámica o embolización arterial se considerarán mensurables siempre que se haya constatado progresión en dichas lesiones y cumplan los criterios de enfermedad mensurable
    3. Podrán participar en el estudio pacientes con infección antigua o activa por el VHC.Los participantes tratados deberán haber completado su tratamiento al menos un mes antes de iniciar la intervención del estudio. Los participantes infectados por el VHC no tratados o tratados de forma incompleta podrán iniciar el tratamiento antiviral contra el VHC si la función hepática se mantiene estable durante al menos tres meses con la intervención del estudio
    4. Podrán participar pacientes con hepatitis B controlada siempre que cumplan los criterios siguientes:
    • Los participantes con infección crónica por el VHB, definida como HBsAg positivo y/o ADN del VHB detectable, deberán recibir tratamiento antiviral contra el VHB durante al menos 4 semanas antes de la primera dosis de la intervención del estudio y la carga viral del VHB deberá ser inferior a 100 UI/ml antes de la primera dosis del tratamiento del estudio.Los participantes en tratamiento activo contra el VHB que presenten una carga viral inferior a 100 UI/ml deberán mantener el mismo tratamiento durante toda la intervención del estudio. El tratamiento antiviral, una vez finalizada la intervención del estudio, deberá seguir las normas locales
    • En los participantes con una infección por el VHB clínicamente resuelta, definida como HBsAg negativo y anticuerpos anti-HBc positivos, y con una carga viral indetectable del VHB en la fase de selección, deberá comprobarse la carga viral del VHB cada 6 semanas, así como administrar tratamiento contra el VHB si la carga viral es superior a 100 UI/ml. El tratamiento antiviral, una vez finalizada la intervención del estudio,deberá seguir las normas locales
    5. Varón o mujer de 18 años o más de edad en el momento de firmar el consentimiento informado
    6. Podrán participar en el estudio varones que se comprometan a todo lo siguiente durante el período de intervención y hasta al menos 120 días después de recibir la última dosis de quimioterapia:
    • Abstenerse de donar semen
    • Abstenerse de mantener relaciones heterosexuales como modo de vida habitual y preferido (abstinencia a largo plazo y constante) y compromiso de mantener la abstinencia
    • Utilizar métodos anticonceptivos a menos que se confirme que presentan azoospermia
    • Los varones participantes deberán comprometerse también a utilizar preservativo masculino en cualquier actividad que permita el paso de eyaculado a otra persona de cualquier sexo
    • El uso de anticonceptivos por los varones deberá cumplir la normativa local sobre métodos anticonceptivos para participantes en estudios clínicos
    7. Una mujer podrá participar si no está embarazada ni en período de lactancia y se cumple al menos una de las condiciones siguientes:
    - No es una mujer en edad fértil (MEF)
    O
    - Es una MEF y utiliza un método anticonceptivo muy eficaz (con un índice de fallos < 1% anual), con baja dependencia de la usuaria, o practica la abstinencia de relaciones heterosexuales como modo de vida preferido y habitual (abstinencia a largo plazo y persistente), según se describe en el Protocolo
    - Las MEF deberán dar negativo en una prueba de embarazo de alta sensibilidad (en orina o suero, según exija la normativa local) en las 24 horas previas a la primera dosis de la intervención del estudio
    - Cuando no pueda confirmarse que el resultado de una prueba en orina es negativo (por ejemplo, resultado ambiguo), será necesario hacer una prueba de embarazo en suero. En tal caso, la participante será excluida si el resultado de la prueba de embarazo en suero es positivo
    8. El participante(o su representante legal cuando proceda)otorga su consentimiento informado por escrito para el estudio
    9. Estado funcional de 0 o 1 según la escala del ECOG en los tres días previos a la primera dosis de la intervención del estudio
    10. Disponibilidad de una muestra de tejido tumoral de archivo o de una biopsia reciente, con aguja gruesa o por escisión, de una lesión tumoral no irradiada previamente (es decir, obtenida para confirmación histológica), para un análisis de biomarcadores. El laboratorio central tendrá que recibir la muestra de tejido tumoral y considerarla adecuada para el análisis de biomarcadores antes de la aleatorización del participante. Se prefieren los bloques de tejido fijados en formol e incluidos en parafina (FFIP) a los cortes para microscopio. Se prefiere el uso de biopsias recientes al tejido de archivo.
    Leer en el protocolo
    E.4Principal exclusion criteria
    1. Has had previous systemic therapy for advanced (metastatic) or unresectable (locallyadvanced) biliary tract cancer (intra-or extra hepatic cholangiocarcinoma or gallbladder cancer), with the exception of adjuvant therapy which is allowed. Adjuvant therapy should have been completed at least 6 months prior to diagnosis of advanced and/or unresectable disease.
    2. Has ampullary cancer.
    3. Has small cell cancer, neuroendocrine tumors, lymphoma, sarcoma and/or Mucinous cystic neoplasms.
    4. Has an active autoimmune disease that has required systemic treatment in the past 2 years (ie, with use of disease modifying agents, corticosteroids or immunosuppressive drugs). Replacement therapy (eg, thyroxine, insulin, or physiologic corticosteroid replacement therapy for adrenal or pituitary insufficiency, etc.) is not considered a form of systemic treatment and is allowed.
    5. Has undergone major surgery and has not recovered adequately from the toxicity to ≤Grade 1 and/or complications from the intervention prior to starting study intervention.
    6. A WOCBP who has a positive urine pregnancy test within 24 hours prior to administration of study intervention. If the urine test is positive or cannot be confirmed as negative, a serum pregnancy test will be required.
    7. Has received prior therapy with an anti-PD-1, anti-PD-L1, or anti PD-L2 agent or with an agent directed to another stimulatory or co-inhibitory T-cell receptor (eg, CTLA-4, OX- 40, CD137).
    8. Has received prior anti-cancer therapy for advanced unresectable biliary tract cancer (intra-or extra hepatic cholangiocarcinoma or gallbladder cancer), including investigational agents within 4 weeks prior to randomization.
    9. Has not recovered (ie, AE ≤Grade 1 or baseline) from AEs due to previously administered chemotherapy. Participants with ≤Grade 2 neuropathy may be eligible based on investigator assessment.
    10. Has received prior radiotherapy within 2 weeks of start of study intervention. Participants must have recovered from all radiation-related toxicities, not require corticosteroids, and have not had radiation pneumonitis. A 1-week washout is permitted for palliative radiation (≤2 weeks of radiotherapy) to non-central nervous system (CNS) disease.
    11. Has received a live vaccine within 30 days prior to the first dose of study intervention.
    12. Is currently participating in or has participated in a study of an investigational agent or has used an investigational device within 4 weeks prior to the first dose of study intervention.
    13. Has a diagnosis of immunodeficiency or is receiving chronic systemic steroid therapy (in dosing exceeding 10 mg daily of prednisone equivalent) or any other form of immunosuppressive therapy within 7 days prior to the first dose of study intervention.
    14. Has a known additional malignancy that is progressing or has required active treatment within the past 3 years.
    15. Has severe hypersensitivity (≥Grade 3) to pembrolizumab, gemcitabine, or cisplatin and/or any of their excipients.
    16. Has a history of (non-infectious) pneumonitis that required steroids or has current pneumonitis.
    17. Has an active infection requiring systemic therapy, with the exception of HBV, and HCV.
    18. Has dual active HBV infection (HBsAg (+) and /or detectable HBV DNA) and HCV infection (anti-HCV Ab (+) and detectable HCV RNA) at study entry.
    19. Has a known history of human immunodeficiency virus (HIV) infection.
    20. Has known active tuberculosis.
    21. Has a known history of, or any evidence of, CNS metastases and/or carcinomatous meningitis, as assessed by local site investigator.
    22. Has a history or current evidence of any condition, (eg, hearing impairment, etc.), therapy, or laboratory abnormality that might confound the results of the study, interfere with the participant's participation for the full duration of the study, or is not in the best interest of the participant to participate, in the opinion of the treating investigator.

    Read in the protocol
    1. Recepción de tratamiento sistémico previo por cáncer de vías biliares (colangiocarcinoma intra o extrahepático o cáncer de vesícula biliar) avanzado (metastásico) o irresecable (localmente avanzado), con la excepción de tratamiento adyuvante, que está permitido. El tratamiento adyuvante deberá haberse completado al menos 6 meses antes del diagnóstico de enfermedad avanzada o irresecable.
    2. Presencia de un cáncer de ampolla de Vater.
    3. Presencia de un cáncer microcítico, tumor neuroendocrino, linfoma, sarcoma y/o neoplasias quísticas mucinosas.
    4. Presencia de una enfermedad autoinmunitaria activa que ha precisado tratamiento sistémico (es decir, fármacos modificadores de la enfermedad, corticoides o inmunodepresores) en los dos últimos años. El tratamiento de reposición (por ejemplo, tiroxina, insulina o corticoides en dosis fisiológicas por insuficiencia suprarrenal o hipofisaria) no se considera una forma de tratamiento sistémico y se permitirá su uso.
    5. Práctica de una intervención de cirugía mayor, sin que el posible participante se haya recuperado debidamente de la toxicidad a un grado ≤ 1 y/o de las complicaciones de la misma, antes de iniciar la intervención del estudio.
    6. Mujer en edad fértil que da positivo en una prueba de embarazo en orina realizada en las 24 horas previas a la administración de la intervención del estudio (véase el apéndice 5). Si el resultado de la prueba en orina es positivo o si no puede confirmarse que sea negativo, será necesario hacer una prueba de embarazo en suero.
    7. Tratamiento previo con un fármaco anti-PD-1, anti-PD-L1 o anti-PD-L2 o con un fármaco dirigido contra otro receptor de los linfocitos T estimulador o coinhibidor (como CTLA-4, OX-40 o CD137).
    8. Tratamiento antineoplásico previo por cáncer de vías biliares (colangiocarcinoma intra o extrahepático o cáncer de vesícula biliar) irresecable avanzado, incluidos fármacos experimentales, en las cuatro semanas previas a la aleatorización.
    9. Ausencia de recuperación (es decir, mejoría hasta un grado ≤ 1 o la situación basal) de AA provocados por la quimioterapia administrada previamente. Podrán participar pacientes con neuropatía de grado ≤ 2 según la evaluación del investigador.
    10. Recepción de radioterapia en las dos semanas previas al comienzo de la intervención del estudio. Los participantes deberán haberse recuperado de toda la toxicidad relacionada con la radioterapia, no precisar corticoides y no haber sufrido una neumonitis por radiación. Se permite un lavado de una semana en caso de radioterapia paliativa (≤ 2 semanas de radioterapia) por enfermedad que no afecte al sistema nervioso central (SNC).
    11. Recepción de una vacuna de microorganismos vivos en los 30 días previos a la administración de la primera dosis de la intervención del estudio.
    12. Participación activa o pasada en un estudio de un fármaco en investigación o uso de un dispositivo en investigación en las cuatro semanas previas a la administración de la primera dosis de la intervención del estudio.
    13. Diagnóstico de inmunodeficiencia o recepción de tratamiento sistémico crónico con esteroides (en dosis superiores a 10 mg diarios de prednisona o un equivalente) o cualquier otra forma de tratamiento inmunodepresor en los siete días previos a la primera dosis de la intervención del estudio.
    14. Presencia de otra neoplasia maligna conocida que esté en progresión o que haya necesitado tratamiento activo en los últimos tres años.
    15. Presencia de hipersensibilidad grave (grado > 3) a pembrolizumab, gemcitabina o cisplatino y/o a cualquiera de sus excipientes.
    16. Antecedentes de neumonitis (no infecciosa) que haya precisado la administración de esteroides o presencia de una neumonitis activa.
    17. Infección activa con necesidad de tratamiento sistémico, a excepción de la infección por el VHB o VHC.
    18. Infección activa doble por el VHB (HBsAg (+) y/o ADN del VHB detectable) y el VHC (anti-VHC (+) y ARN del VHC detectable) en el momento de incorporación al estudio.
    19. Antecedentes de infección por el virus de la inmunodeficiencia humana (VIH).
    Nota: No será necesario realizar pruebas del VIH a menos que lo exijan las autoridades sanitarias locales.
    20. Presencia de tuberculosis activa (Bacillus tuberculosis). Nota: No será necesario realizar pruebas de tuberculosis H a menos que lo exijan las autoridades sanitarias locales.
    21. Antecedentes conocidos o cualquier indicio de metástasis en el SNC y/o meningitis carcinomatosa, según la evaluación del investigador del centro local.
    22. Antecedentes o datos presentes de cualquier proceso (por ejemplo, hipoacusia, etc.), tratamiento o anomalía analítica que, en opinión del investigador responsable del tratamiento, podría confundir los resultados del estudio, dificultar la participación durante la totalidad del estudio o motivar que la participación no sea lo más conveniente para el posible participante.

    Leer en el protocolo
    E.5 End points
    E.5.1Primary end point(s)
    1. Progression-free Survival (PFS) per Response Evaluation Criteria in Solid Tumors (RECIST) 1.1 as Assessed by Blinded Independent Central Review (BICR)
    2. Overall Survival (OS)
    1. Supervivencia libre de progresión (PFS) por criterios de evaluación de respuesta en tumores sólidos (RECIST)
    2. Supervivencia global (SG)
    E.5.1.1Timepoint(s) of evaluation of this end point
    1. Up to 48 months
    2. Up to 48 months
    1. Hasta 48 meses
    2. Hasta 48 meses
    E.5.2Secondary end point(s)
    1. Objective Response Rate (ORR) per RECIST 1.1 as Assessed by BICR
    2. Duration of Response (DOR) per RECIST 1.1 as Assessed by BICR
    3. Number of Participants Who Experienced One or More Adverse Events (AEs)
    4. Number of Participants Who Discontinued Study Intervention Due to an Adverse Event (AE)
    1. Tasa de respuesta objetiva (TRO) por RECIST 1.1 evaluado por BICR
    2. Duración de la respuesta (DR) por RECIST 1.1 evaluado por BICR
    3. Número de participantes que experimentaron uno o más acontecimientos adversos (AA)
    4. Número de participantes que interrumpieron la intervención del estudio debido a un acontecimiento adverso (AA)
    E.5.2.1Timepoint(s) of evaluation of this end point
    1. Up to 48 months
    2. Up to 48 months
    3. Up to 48 months
    4. Up to 48 months
    1. Hasta 48 meses
    2. Hasta 48 meses
    3. Hasta 48 meses
    4. Hasta 48 meses
    E.6 and E.7 Scope of the trial
    E.6Scope of the trial
    E.6.1Diagnosis No
    E.6.2Prophylaxis No
    E.6.3Therapy Yes
    E.6.4Safety Yes
    E.6.5Efficacy Yes
    E.6.6Pharmacokinetic Yes
    E.6.7Pharmacodynamic Yes
    E.6.8Bioequivalence No
    E.6.9Dose response No
    E.6.10Pharmacogenetic Yes
    E.6.11Pharmacogenomic Yes
    E.6.12Pharmacoeconomic No
    E.6.13Others Yes
    E.6.13.1Other scope of the trial description
    Health Utility Scores; anti-MK3475 antibody levels
    Utilidad de las puntuaciones de salud; los niveles de anticuerpos anti-MK3475
    E.7Trial type and phase
    E.7.1Human pharmacology (Phase I) No
    E.7.1.1First administration to humans No
    E.7.1.2Bioequivalence study No
    E.7.1.3Other No
    E.7.1.3.1Other trial type description
    E.7.2Therapeutic exploratory (Phase II) No
    E.7.3Therapeutic confirmatory (Phase III) Yes
    E.7.4Therapeutic use (Phase IV) No
    E.8 Design of the trial
    E.8.1Controlled Yes
    E.8.1.1Randomised Yes
    E.8.1.2Open No
    E.8.1.3Single blind No
    E.8.1.4Double blind Yes
    E.8.1.5Parallel group Yes
    E.8.1.6Cross over No
    E.8.1.7Other No
    E.8.2 Comparator of controlled trial
    E.8.2.1Other medicinal product(s) No
    E.8.2.2Placebo Yes
    E.8.2.3Other No
    E.8.2.4Number of treatment arms in the trial2
    E.8.3 The trial involves single site in the Member State concerned No
    E.8.4 The trial involves multiple sites in the Member State concerned Yes
    E.8.4.1Number of sites anticipated in Member State concerned5
    E.8.5The trial involves multiple Member States Yes
    E.8.5.1Number of sites anticipated in the EEA69
    E.8.6 Trial involving sites outside the EEA
    E.8.6.1Trial being conducted both within and outside the EEA Yes
    E.8.6.2Trial being conducted completely outside of the EEA No
    E.8.6.3If E.8.6.1 or E.8.6.2 are Yes, specify the regions in which trial sites are planned
    Argentina
    Australia
    Belgium
    Brazil
    Canada
    Chile
    China
    France
    Germany
    Hong Kong
    Ireland
    Israel
    Italy
    Japan
    Korea, Republic of
    Malaysia
    Netherlands
    New Zealand
    Spain
    Taiwan
    Thailand
    Turkey
    United Kingdom
    United States
    E.8.7Trial has a data monitoring committee Yes
    E.8.8 Definition of the end of the trial and justification where it is not the last visit of the last subject undergoing the trial
    LVLS
    LVLS
    E.8.9 Initial estimate of the duration of the trial
    E.8.9.1In the Member State concerned years3
    E.8.9.1In the Member State concerned months10
    E.8.9.1In the Member State concerned days
    E.8.9.2In all countries concerned by the trial years3
    E.8.9.2In all countries concerned by the trial months10
    F. Population of Trial Subjects
    F.1 Age Range
    F.1.1Trial has subjects under 18 No
    F.1.1.1In Utero No
    F.1.1.2Preterm newborn infants (up to gestational age < 37 weeks) No
    F.1.1.3Newborns (0-27 days) No
    F.1.1.4Infants and toddlers (28 days-23 months) No
    F.1.1.5Children (2-11years) No
    F.1.1.6Adolescents (12-17 years) No
    F.1.2Adults (18-64 years) Yes
    F.1.2.1Number of subjects for this age range: 397
    F.1.3Elderly (>=65 years) Yes
    F.1.3.1Number of subjects for this age range: 391
    F.2 Gender
    F.2.1Female Yes
    F.2.2Male Yes
    F.3 Group of trial subjects
    F.3.1Healthy volunteers No
    F.3.2Patients Yes
    F.3.3Specific vulnerable populations Yes
    F.3.3.1Women of childbearing potential not using contraception No
    F.3.3.2Women of child-bearing potential using contraception Yes
    F.3.3.3Pregnant women No
    F.3.3.4Nursing women No
    F.3.3.5Emergency situation No
    F.3.3.6Subjects incapable of giving consent personally No
    F.3.3.7Others No
    F.4 Planned number of subjects to be included
    F.4.1In the member state18
    F.4.2 For a multinational trial
    F.4.2.1In the EEA 237
    F.4.2.2In the whole clinical trial 788
    F.5 Plans for treatment or care after the subject has ended the participation in the trial (if it is different from the expected normal treatment of that condition)
    Upon study completion, participants are discontinued and may be enrolled in a pembrolizumab extension study.
    Al finalizar el estudio, aquellos participantes que hayan discontinuado y puedan participar en un estudio de extensión de pembrolizumab.
    G. Investigator Networks to be involved in the Trial
    N. Review by the Competent Authority or Ethics Committee in the country concerned
    N.Competent Authority Decision Authorised
    N.Date of Competent Authority Decision2019-09-27
    N.Ethics Committee Opinion of the trial applicationFavourable
    N.Ethics Committee Opinion: Reason(s) for unfavourable opinion
    N.Date of Ethics Committee Opinion2019-09-04
    P. End of Trial
    P.End of Trial StatusOngoing
    As of 1.2.2020, the UK is no longer an EU Member State. However, EU law still applies to the UK during the transition period
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